Inflammation is the foundation for cancer and degenerative/autoimmune diseases. Small changes in diet and exercise, e.g. omega-3 oils, vitamin D, low starch, and maintaining muscle mass, can dramatically alter predisposition to disease and aging, and minimize the negative impact of genetic risks. Based on my experience in biological research, I am trying to explain how the anti-inflammatory diet and lifestyle combat disease. 190 more articles at http://coolinginflammation.blogspot.com

Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:

Friday, December 31, 2010

A reader (Jay Bryant) recently pointed out a PNAS article on the structure of a bacterial enzyme that uses sucrose to make the glucan matrix of dental biofilms. This article released a cascade of associations in my mind and illustrated why honey does not contribute to dental plaques, but is antimicrobial and aids wound healing. People forget that sugars combine both hydrophilic and hydrophobic properties, and thereby act as soaps.

The starting point of the chemical versatility of carbohydrates is the inability of the central portion of a sugar ring structure to form hydrogen bonds. Each sugar is made of a linear chain of carbon atoms with each carbon linked also to a hydrogen and a hydroxyl. Only the hydroxyl can participate in hydrogen bonds, so each carbon has a hydrophilic side (bonds with water to make hydrogen bonds) and a hydrophobic side (that makes van der Waals bonds with other hydrophobic molecules.) The sugars circularize and the rings have faces that are predominantly hydrophobic and perimeters with hydroxyls that are hydrophilic. Polysaccharides (long chains of sugars), such as cellulose, can sometimes form long fibers that form a hydrophobic context for hydrogen bonds between the hydroxyls of adjacent polymers. These cellulose fibers are very resistant to chemical or biological attack and accumulate as the most abundant biological molecules on Earth.

The PNAS article provides another example of how protein enzymes interact with carbohydrates, in this case sucrose and a polymer of glucose. Typical weak bonds between the amino acid residues of proteins and other molecules are hydrogen, ionic or van der Waals bonds with energies of a couple of kcals/mol. In contrast, the bonding of the hydrophobic face of a sugar to the hydrophobic face of an hydrophobic amino acid, e.g. tryptophan, phenylalanine, histidine, lysine or arginine, releases more than ten kcals/mol of energy. Thus, the structure of the bacterial enzyme that makes biofilm glucan chains from dietary sucrose, the sucrose is bound to the enzyme on the face of a prominent tryptophan. Examination of enzymes that bind to polysaccharides will show a series of tryptophans arrayed across the surface of the enzymes with spacing appropriate to bind to the individual sugars of the polysaccharide.

Biofilms are communities of multiple species of bacteria held together by a polysaccharide matrix. In the case of dental plaque, the polysaccharide is made of glucose links, whereas many other matrix polysaccharides are negatively charged and held together by positively charged metal ions. The bacteria bind to the polysaccharides using protein receptors that exploit the display of hydrophobic binding sites of the polysaccharides. It takes energy to make polysaccharides and the dental plaque bacteria use the energy already expended in the formation of sucrose to produce a polymer of glucose, an alpha-glucan, and free fructose. Thus, sucrose is essential in forming this type of biofilm and without this sugar, the dental plaque cannot form. Milk lactose, or glucose would be a more appropriate sweetener. Unfortunately, high fructose corn syrup would be a poor substitute, because of the high liver toxicity of the fructose (it causes fatty liver, just like alcohol) and very high activity in forming advanced glycation end products (AGEs), which contribute to the symptoms of diabetics.

Honey seems to be magical, because at low concentrations the sugars present in honey (mostly glucose and fructose, and not sucrose) are nutrients for bacteria, but at high concentrations honey is anti-bacterial and useful as a wound treatment. I think that the explanation for its antimicrobial activity is that sugars are amphipathic, that is they have both hydrophilic and hydrophobic properties, just like soap, and at high concentrations they kill bacteria, just as soaps at high concentrations kill bacteria. In fact, the gentle soaplike properties of sugars are exploited experimentally to dissolve proteins that are normally embedded in cellular membranes. This explanation predicts that corn syrup, which can also be used to form very stable soap bubbles, should also be useful in wound healing.

Tuesday, August 3, 2010

I think that I should explain, if it is not obvious, why I keep bringing up breastfeeding/infant nutrition on this blog about diet, inflammation and disease. The starting point is that infants need nutrition, protection from disease and continued normal development or they won’t be able to reproduce. That means that milk is the focal point of a lot of natural selection and absence of the natural functions of milk, e.g. use of formula, would be expected to lead to inflammation and disease, which it does. Analysis of milk and how formula makes infants susceptible to disease and alters normal development, provides an extreme example of the interactions of diet, gut flora and the immune system.

Since this is World Breastfeeding Week and my wife is an Internationally Board Certified Lactation Consultant, I think that writing a few articles on milk is good for my health.

I find it amazing that supplements are encouraged for exclusively breastfeeding infants. It doesn’t make sense to suspect that breast milk is inadequate and why is formula fortified with ingredients at ten to a hundred times the levels in breast milk? The answer is in the infant gut flora and perhaps in poor maternal nutrition/gut flora.

Mother’s Milk Promotes Normal Infant Gut Flora -- Bifidobacteria

The normal infant gut flora is very simple, Bifidobacteria. Adults have gut flora composed of hundreds of different species of bacteria and infants have just Bifidobacteria. The name of the infant bacterium should be familiar if you read labels on yogurt. Bifidobacteria are common probiotics. That also explains why the diapers of exclusively breast fed babies smell like yogurt.

Formula Promotes Adult Gut Flora

One bottle of formula kills the Bifidobacteria and replaces it with adult gut bacteria. The diapers are forever changed, because the adult gut flora is very persistent. The presence of the adult gut flora also explains why formula has the high levels of supplements. The adult gut flora consumes the supplements and leaves only tiny amounts for the infant. All of the breast milk nutrients go to the baby if only Bifidobacteria is present, but after the adult gut flora are established much higher levels are needed and the infant may still be deficient. Adult, formula-supported gut flora also digest antibodies and other protective factors in mother’s milk.

Supplement Mothers to Improve Infant Nutrition

Modern mothers are also eating modern diets that produce deficiencies. Chronic diet-based inflammation leads to a compromised ability to produce vitamin D in sunlight. Nursing mothers with poor diets may not be transferring enough vitamin D to their nursing babies. Since formula and the adult gut flora that it stimulates, causes gut inflammation, I suspect that formula fed infants are also compromised in their ability to produce their own vitamin D in sunlight. It makes more sense to supplement mothers than babies.

Formula Is not Breast Milk, It’s Not Even Close

Formula is cheap to produce, but expensive to buy. Formula is promoted as the next best substitute for milk from a baby’s own mother, but that isn’t true either. The next best alternative is mother’s milk from a certified human milk bank. It is available at a reasonable cost. Hospitals should know better and provide the only appropriate alternative. Early formula use dramatically increases healthcare costs.

Formula Lacks the Oligosaccharides Needed to Support only Bifidobacter

Fructose oligosaccharides (FOS) and other short chains of sugars are being promoted to support the growth of beneficial gut flora. These oligosaccharides do promote the growth of adult gut flora, but not just infant Bifidobacteria. Formula plus FOS and/or other prebiotic oligosaccharides other than those present in human milk support the growth of bacteria that rob nutrients from and degrade the protective components of breast milk. If the diaper smells like adult gut flora, then the baby was not fed mother’s milk.

Development of Gut and Brain

The newborn gut and brain are only partially developed. Mother’s milk is needed to supply growth factors to close and differentiate the gut epithelium, and long chain omega-3 fatty acids for brain growth. Formula may eventually be supplemented with the needed fatty acids, but the growth factors/hormones present in mother’s milk will not be provided in formula. Recent studies have shown that hundreds of different genes are activated in gut cells from infants fed either breast milk or formula. Formula leaves the gut leaky and fails to stimulate the development of the immune system that is dependent on interaction with normal infant gut flora. These dysfunctions partially explain the increased (10X to 100X) gut and respiratory infections resulting from formula use. The reduced brain development with formula explains the five point reduction in IQ of formula fed infants.

Friday, July 30, 2010

Grain/gluten intolerance, celiac is an immunological attack on the small intestines with increased risk for numerous autoimmune diseases. Hashimoto’s thyroiditis is a common sequela of celiac and the two diseases share the same autoantigen, tissue transglutaminase (tTG). Thus, the development of celiac and the production of antibodies to the tTG produced in the intestines, results in a subsequent immunological attack on other tissues that produce lots of tTG, e.g. the thyroid. Gluten intolerance, because of its attack on the intestines and the proximity of a major part of the immune system (GALT), may play a major role as the foundation for autoimmune diseases.

Gluten Intolerance First Step in Autoimmune Diseases

Celiac may also lead to herpatic lesions of the skin, dermatitis herpetiformis and loss of hair, alopecia. In these cases, the autoantigen is peroxiredoxin, an enzyme that eliminates hydrogen peroxide produced as a result of accumulation of reactive oxygen species, e.g. superoxide, associated with inflammation. Peroxiredoxin is also implicated as an autoantigen in periodontal disease, suggesting that celiac may also contribute to dental gum inflammation.

Peroxiredoxin 5 Gene Associated with Alopecia Risk

A recent study (see ref. below) of genes associated with alopecia identified genes involved in Treg and Th-17 development, as well as peroxiredoxin 5 as contributors. As expected, several genes involved in antigen presentation (HLA-DRA, HLA-DQA) were also identified. Th-17 lymphocytes are involved in immune attacks on self tissue, i.e. autoimmune diseases, such as alopecia, in which hair follicles are attacked by the immune system. Tregs control immune attacks on self tissues. Peroxiredoxin is an autoantigen and is produced in elevated amounts around hair follicles attacked in alopecia.

Basic Amino Acids of Peroxiredoxin as Expected for Autoantigen

I checked the amino acid sequence of human peroxiredoxin 5 and found an alternative (-nrrlkrfsmv-) to the triplet of basic amino acids that I expect for an autoantigen. In this case there are two adjacent pairs of basic amino acids (blue rr and kr) that I think precipitate immunological presentation of peroxiredoxin. Peroxiredoxins are produced in response to oxidative stress at sites of inflammation and the presence of celiac compromises the gut associated immune system (GALT) that provides Tregs to restrict autoimmunity, so celiac sets the stage for peroxiredoxin presentation to the immune system and for subsequent production of anti-peroxiredoxin antibodies, autoimmunity and destruction of hair follicles, alopecia.

Anti-Inflammatory Diet Should Avoid and Treat Autoimmunity

Control of autoimmune diseases mediated by peroxiredoxin should benefit from a reduction in the conditions that spawned the diseases:

supplements to compensate for depletion of vitamin C and glutathione by oxidative stress, e.g. vitamin C and acetylcysteine (NAC)

Th-17 and Tregs in HIV Infections

Th-17 cells are also reduced by HIV infection, producing susceptibility to infection, but this infection should also reduce autoimmune disease. The reduction in Th-17 also may be a consequence of problems in the GALT. Therapy for HIV infection should also include diet considerations to increase Th-17 and also Tregs to reduce autoimmune diseases due to unbalanced Th-17.

Thursday, June 17, 2010

Speculation on the cause of infant reactions to cow’s milk in formula or transmitted into mother’s milk. Are mother’s priming their newborns in utero with antibodies to react to non-human sugars (Neu5Gc)?

Sialic Acids Mark the Surface of Human Cells

Human cells are covered with a forest of long and short carbohydrates, polysaccharides and oligosaccharides resp., which control the interaction of the cells with the outside world. The sugars exposed on the ends of these sugar chains are sialic acids. It is not surprising that pathogenic viruses and bacteria target sialic acids as the first step in attacking human cells and that policing immune cells avoid attacking their own cells by recognizing the sialic acids. The surprise is that essentially all other mammals have the same two sialic acids, Neu5Ac and Neu5Gc, but humans have only Neu5Ac. Meat and cow’s milk have both. Babies and mother’s milk should have only Neu5Ac.

Evolution to Lose Neu5Gc to Avoid Pathogens

Surviving defective remnants of genes needed to make Neu5Gc suggest that loss of Neu5Gc was an adaptation to avoid general mammalian pathogens and to facilitate brain development. One of the limitations of using other mammals as models of human diseases is the differences in sialic acids that are commonly used for initial docking of pathogens on human cells. Other mammals have different forms of malaria than humans and we are well aware that influenza adapted to birds and pigs does not infect humans without adjusting to the lack of Neu5Gc.

Antibodies Against Neu5Gc

Humans make antibodies to Neu5Gc when injected with blood products from other mammals. A sudden change from a long term vegan diet to a meat diet can also lead to the production of anti-Neu5Gc antibodies. These types of antibodies may contribute to some types of non-lactose milk intolerance/allergies.

Neu5Gc from Cow’s Milk Gangliosides to Mother’s Milk

A significant problem in infant health is the reaction of the infant with abdominal distress after eating cow’s milk-based formula or in some cases from breastfeeding after the mother has eaten milk or other dairy products. Milk oligosaccharides, proteins and lipids have Neu5Gc. It is unlikely that cow’s milk proteins or oligosaccharides can move from the mother’s intestines to her breast milk, but it is possible that Neu5Gc attached to fatty acids in the form of gangliosides may be transferred to breast milk.

Mother’s Anti-Neu5Gc in Infants Gut Reacts with Cow Neu5Gc

If cow’s milk gangliosides are the source of Neu5Gc in breastmilk, then how do the infants develop antibodies to these relatively rare antigens? Babies receive all of their antibodies from their mother until their immune systems start to develop at about six months of age. The answer is hinted at by the observation of a mother whose exclusively breastfed infant developed sensitivity to breast milk after the mother ate dairy products. The mother reported that she shifted from a long term vegan diet to a meat diet to improve her nutrition during her pregnancy. It is also likely that she produced IgE antibodies to Neu5Gc, which were then transferred to her baby across the placenta during gestation.

Anti-Neu5Gc Antibodies May Explain Infant Milk Intolerance and Colic

Infants with anti-Neu5Gc antibodies obtained from their mother during gestation in utero, will have mast cells in the lining of their gut that are primed to react to Neu5Gc in cow’s milk present as components in formula or in trace amounts transferred into breast milk. Infants may respond to these immunological reactions with a variety of symptoms, including those observed as rejection of formula or breast milk after the mother has eaten dairy products or as colic.

Friday, May 28, 2010

Babies born prematurely are at risk of a serious bacterial infection of the intestines, necrotizing enterocolitis (NEC), that can be prevented if formula based on cow’s milk products is avoided and human milk is used for all feedings.

Human Milk Protects Against Formula Based NEC

Feeding low birth weight, premature babies formula made from cow’s milk increases their risk of NEC ten fold. Replacement of some of the cow’s milk formula with human milk from a milk bank reduces NEC.

Human Milk and Cow’s Milk Are Very Different

What is present in human milk that protects against NEC? The major components in milk are proteins, lactose, fats and oligosaccharides (short to medium length chains of sugars.) Human milk and cow’s milk have the same amount of fat (35 grams/liter) and about the same amount of lactose (65 vs. 45 g/l) and protein (10 vs. 35 g/l). The big difference is in the amount (5-10 vs. 0.05 g/l) and quality of oligosaccharides. Human milk has more than 100 times the amount of oligosaccharides as cow’s milk. That also means that about 10% of the carbohydrates in human milk are non-nutritive human milk oligosaccharides (HMOs).

HMOs Are Not FOS

Human milk oligosaccharides are complex, with over 200 different structures identified so far. Essentially they are made up of a lactose (a disaccharide consisting of galactose linked to glucose) extended by different numbers of N-acetyllactosamine (lactose with a modified glucose) and a few other sugars attached a various locations. A different enzyme is used for each modification and the synthesis of these oligosaccharides has not yet been figured out in detail. More than a dozen different genes are devoted to the synthesis of these oligosaccharides. These oligosaccharides are not structurally or functionally related to the frucose oligosaccharides used as prebiotics.

HMOs Are Prebiotic and Stop NEC

Human milk oligosaccharides have been tested both for their ability to act as prebiotics to encourage the development of normal baby gut flora and to suppress NEC. The HMOs were found to be the elusive bifidus factor that stops the development of adult gut flora and facilitates only the development of the Biﬁdobacterium biﬁdum monoculture found in exclusively breastfed babies. HMOs also reduce NEC in the same way as whole human milk. Another interesting aspect of HMOs is that they modify the oligosaccharides produced on the surface of baby intestinal cells. Babies fed human milk also secrete HMOs in their urine, indicating that ingested HMOs are absorbed in the intestines and reach the blood stream.

Neonatal Nurseries Should Use Only Human Milk

Human milk is now available to neonatal intensive care nurseries through milk banks and purified components of human milk are also available to supplement feedings for very low birth weight premature babies. Nursing is still best for baby and mother, but those mothers who choose not to nurse need not compromise the health and development of their babies by using cow’s milk-based formula or supplements. Every dollar spent on pasteurized donor milk ($3/oz.) reduces costs in neonatal intensive care units by more than ten dollars. It seems to be time to eliminate the added risks of formula use in hospitals and provide every baby with a healthy start and normal gut flora by only using human milk products in hospitals.

Saturday, May 15, 2010

Contributions of genetic alleles to disease are useful for understanding, but not in predicting disease. Diet and lifestyle are the major determinants of disease and not genes for most common diseases.

OTC Genetic Screening Kits

A recent headline touted the availability of a kit at Walgreens to screen for “predisposition” to a hundred common diseases. A few months earlier, scientists admitted that after lengthy examination of a dozen major diseases, the genetic contribution was negligible. It may now be possible to cheaply (less than $25,000) determine the sequence of the entire genome of an individual or even more cheaply test for the presence of particular genetic alleles, but that information is useless compared to diet for predicting if the person will actually get the disease. The screening kits were pulled before they reached the shelves.

Gut Flora Dominates Gut Genotype

I think that the reason why an individual’s genes don’t dominate health issues, is because the composition of meals dominates the development of the gut flora community and it is the interaction between the gut and its bacteria that dominates health. The genes of the individual are just not that important in determining disease.

You Are What You Ate

For each individual, the meals eaten over the last years have cultivated the existing gut flora, composed of hundreds of different species of bacteria with unique metabolic capabilities to digest unusual meal molecules and modulate the immune system. Molecular communication between gut and the bacteria in intimate contact determine food intolerance, allergies, autoimmunity and many other disease processes. Healthy eating produces a healthy gut flora and bad meal decisions can lead to unhealthy gut flora and the modern litany of inflammatory ailments. Some genes may mitigate or magnify the development of unhealthy gut flora, but it is difficult to be healthy with compromised gut flora.

Antibiotic Disruption of Gut Flora Trumps Good Genes

It doesn’t matter if there are great genes to help avoid disease, if the function of those genes is compromised by gut dysbiosis, a lack of functional gut flora. Many antibiotic treatments, e.g. for acne, act by attacking the gut flora that support a specific portion of the immune system. Deletion of this function causes cosmetic improvement, e.g. relief of skin inflammation, but at the expense of producing a dysfunctional immune system that may lead to other diseases. Presence or absence of healthy genes can be made irrelevant, if the gut flora is dysfunctional.

Friday, April 30, 2010

Diet selects for the bacteria that grow in the GI track and control the development of the immune system. Diet-based inflammation produces aging symptoms.

Returning to the Subject of Aging

I want to return to the subject of aging. A year and a half ago I wrote, “You don’t wear out, you flame out.” I still think that is true, but I need to update that idea of inflammation and aging to include diet, gut flora and immune system development. So here is my old article with a new focus on the gut.

Wearing Out Only Happens with Inflammation

I don’t think that aging happens -- most symptoms associated with aging are just medically mismanaged chronic inflammation. The major observations are that older people have more degenerative/autoimmune diseases and they suffer from fewer infectious diseases. The typical explanation is that the bodies of older people have figured out infections with an experienced immune system and that mechanical damage takes its toll over time -- joints wear out. I think that there may be a minor amount of truth in this cultural perspective, but there is something more profound at work, sarcopenia combined with a compromised gut flora.

Replacing Muscle with Visceral Fat Is Inflammatory

Sarcopenia (muscle loss) is the gradual loss of muscle and replacement by fat. Thus, by age fifty most people are physically less active and even if they appear to have the same weight and shape as in their active youth, the muscle of their abdomens and limbs has been partially replaced with fat. This fat, as in those who are obese, releases inflammatory cytokines into the circulation and the body reacts as if it has a low grade infection.

Chronic Inflammation Taxes Immune System

Senior citizens are constantly expending energy and taxing their immune system by chronic inflammation. As a result they get fewer infections, but the chronic inflammation provides the foundation for cancer and autoimmune diseases. Their bodies aren’t mechanically wearing out, but they are wearing out by over use of the immune system.

Aging Symptoms Are Inflammation Symptoms

Those seniors who are physically active and eat an anti-inflammatory diet, do not appear to age as fast as those who are sedentary, obese and display the typical symptoms of chronic inflammation, the metabolic syndrome. Most of the characteristics associated with advancing years are merely symptoms of poorly managed chronic inflammation that can be reversed by an anti-inflammatory diet and exercise.

Diet Determines Gut Flora

Diet also contributes to aging, because diet controls development of gut flora and gut flora control development of the immune system. The gut flora of an individual reflect the bacteria that have entered the GI tract, nutrients available to the bacteria in previous meals, bacterial growth regulators released by the gut, exposure to antibiotics, exposure to phytochemicals and gut transit time.

Gut Flora Is Diverse and Adaptable

Gut flora appears to be amazingly diverse from individual to individual with thousands of bacterial species inhabiting humans worldwide and about 150 species in each individual. The same species remain in an individual for long periods of time regardless of diet. The dominance of particular species depends on recent diet. Major changes can result from antibiotics or gut diseases, e.g. Crohn’s.

Constipation Means Dysfunctional Gut Flora

Bowel stools are made up predominantly of bacteria and not undigested plant parts, i.e. fiber. Fiber is made up of plant polysaccharides that are not digested by salivary, stomach or pancreatic enzymes, e.g. proteases and amylases that degrade proteins and starch. Fiber polysaccharides pass into the colon where they are digested by gut flora. People with constipation usually have disrupted gut flora, e.g. wiped out by antibiotics, and so the minimal volume of remaining undigested fiber is all that passes out in compact, dehydrated lumps. If gut flora have been exposed to a particular type of fiber and bacteria having the needed enzymes have been brought into the gut previously, then the fiber is digested to sugars that feed the gut bacteria. The increased population of bacteria is what makes up normal, hydrated bowel stools.

Gut Flora Changes Slowly to New Foods (Polysaccharides)

Bacteria grow quickly and with ample nutrients gut bacteria can double in number in about an hour. Bacterial species are usually defined by the ability to utilize various carbohydrates or polysaccharides as nutrients. Depending on the food eaten, nutrients favor the growth of particular bacterial species and the gut flora population changes dynamically. New species are incorporated into the gut flora only if they find their way into the gut on food, e.g. riding on fresh, uncooked vegetables, and food provides nutrients that can permit the new bacteria to grow. It will take several meals for new bacteria to reach appreciable numbers. In the mean time the new fiber may be partially degraded and produce chemicals that disrupt other gut flora and cause bloating symptoms of food intolerance. This is not an allergic reaction of the immune system. It just takes time and persistence to permit the gut flora to adapt. Most people systematically make themselves intolerant to particular foods by over-reacting to initial maladaption of their gut flora to the new food. If they persisted with progressive exposure to diverse foods, their gut flora would adapt.

Simplified Aging Gut Flora Contributes to Inflammation

People of increasing age who maintain a diverse, anti-inflammatory diet and maintain muscle mass by weight-bearing exercise, avoid age-related inflammation and disease, i.e. they age more slowly. Conversely, those who simplify their diets by eating processed foods high in starch and vegetable oils, show symptoms normally associated with advanced age, even when young. The aging diet is inflammatory and it also produces a gut flora which is different from the youthful.

Aging Gut Flora Contributes to Disease

Constipation is an extreme example of dysfunctional gut flora and since gut bacteria are needed for the normal development of the immune system that is located in the lining of the small intestines, constipation is also an indicator of a compromised immune system. Aging is frequently accompanied by digestive problems with one extreme being constipation. It should not be surprising that individuals with compromised immune systems also develop numerous degenerative diseases indicative of a lack in the immunological tolerance systems that develop in the gut in response to normal gut flora. Constipation and digestive problems are not normal signs of aging.

Eliminate Symptoms of Aging by Cultivating Gut Flora

A healthy diet, healthy gut flora, and a competent immune system are all tightly connected. The typical symptoms of aging merely reflect an unhealthy diet and lifestyle that leads to chronic inflammation, a compromised immune system and disease. The process of aging can be slowed by attention to the next meal. Most people who fail to be healthy and active well into their 80’s are simply victims of bad choices (or of bad medical advice.)

Thursday, April 22, 2010

Cattle Are Finished by Selective Killing of Gut Flora. The Sickened Animals Store Fat that Grills Great. People Get Metabolic Syndrome.

The likening of modern humans to potatoes sacked out on a couch is misleading. The obesity epidemic linked to diets of processed foods more closely resembles the stumbling progression of cattle to abattoir. Antibiotics and diet systematically lead in both feedlot and food court to gut dysbiosis, immune system failure, hormone disruption, rampant fat accumulation, physical inactivity, depression and the modern suite of chronic diseases. Healthcare costs escalate, but vet bills, in contrast, are forestalled by a captive bolt pistol.

Background Observations

Antibiotics kill bacteria and not humans, because the bacteria have different machinery for making proteins, nucleic acids and cell walls.

Antibiotics kill bacterial pathogens and not viruses or fungi.

Antibiotics kill helpful bacteria in the gut (gut flora) even more readily than pathogens.

Antibiotics are used in meat production to alter gut flora to change animal metabolism; e.g. cattle treated with antibiotics gain fat. Protection from disease is secondary.

The appendix stores gut bacteria as a reserve to replenish gut flora following diarrhea.

Diseases based on inflammation and immune system intolerance result from gut dysbiosis (inadequate gut bacteria).

Antibiotics Kill Good Bacteria

This is a rant about antibiotics, not about humane actions. Humane actions are not the point here, since I am talking about health care and not treatment of agricultural animals. I am pleading for the rights of gut flora everywhere and antibiotics are the casual killers. Compromised gut flora is collateral damage in attempting to eliminate bacteria characterized as pathogens. Every time the pediatrician treats the mother by acceding to her pleas for an antibiotic prescription to silence a howling ear ache and get a good night’s sleep, or the dermatologist treats teen acne with antibiotics, billions and billions of domesticated bacteria die.

Constipation Is a Sign

Countless hours are wasted waiting, because antibiotic-depleted gut flora cannot hydrate and form normal stools. Probiotics are gulped down, but they supply only a handful of the hundreds of bacterial species that are needed for health. Yeasts and other fungi that are naturally resistant to antibiotics quickly replace the lost beneficial bacteria in the gut, vagina and on other body surfaces. Surcease for simple sorrows leads to lingering and lasting laminations. Don’t mess with mother nurture.

Damage of Antibiotic Use Is Slow

Most of the impact of antibiotic annihilation of bacteria normally present in humans is unobserved, because the deleterious effects lag months behind the initial treatment. After all, cattle treated with antibiotics to restructure their gut flora to induce bovine obesity, appear to thrive as they rapidly gain weight and avoid symptoms of infectious diseases. Humans on antibiotics also display fewer dental and incidental infections. Constipation is not a high price to pay for a better mirror image.

Antibiotics Compromise the Immune System

Unfortunately, allergies, autoimmune diseases, degenerative diseases and cancers are not usually linked to prior use of antibiotics. There is no evidence that gut flora recovers after antibiotic treatment, but constipation as a consequence of chronic antibiotic use is a common indicator of gut dysbiosis, collapse of normal gut flora bacterial communities. The harbingers of inflammatory and degenerative diseases are present, but are usually discounted, because they are a common consequence of the Western diet.

Food Intolerance Reveals Inadequacies in Gut Flora

Food intolerance is a sign of depleted gut flora diversity. Gut flora have hundreds of genes that can break down a huge diversity of polysaccharides derived from plant cell walls. Gut flora of Japanese who routinely consume kelp have specialized enzymes to hydrolyze unusual algal sulfated polysaccharides. Essentially all of the polysaccharides in plant fiber can be consumed by bacteria in the anaerobic environment of the colon. Inability of individuals to digest particular food components usually results from a deficiency of the gut flora and an indication of a history of dietary simplification and antibiotic use. Lactose intolerance, for example, results from depletion of lactose-degrading bacteria from the gut flora and can be remedied by simply eating lactose with probiotics for a couple of weeks. Gut flora can adapt, but they need persistent exposure to diverse, i.e. non-processed, food.

Antibiotic Allergies Are Natural

Allergies develop from a combination of inflammation and compromised immunological tolerance. Inflammation heightens processing of antigens for presentation to the immune systems, whereas loss of immunological tolerance means that aggressive immune responses are inadequately controlled. Thus, innocuous environmental molecules are incorrectly recognized as pathogen components. Allergies to antibiotics, such as penicillin, make sense, because the antibiotic is used to treat inflammatory infections and the antibiotic treatment eliminates the gut bacteria that are needed to develop gut lymphocytes (Tregs) to produce tolerance. Antibiotics lay the foundation for immune system dysfunction that is central to many chronic diseases.

Tuesday, April 13, 2010

Japanese Gain Ability to Digest Algal Polysaccharides from Marine Bacteria
Gut flora adapt to the food nutrients that are prevalent in different parts of the world. Bacteria able to digest unusual nutrients, such as the sulfated porphyrans found in seaweed eaten in Japanese cuisine, are also consumed along with algae. Formation of bacterial biofilms triggers the exchange of genes among gut bacteria and the acquisition of new polysaccharide-degrading enzyme activities.

Gut Flora Adapts to Diet
The million or so genes of the thousands of bacterial species found in the guts of humans around the world are adapted to the diet of each of those individuals. Each individual gut harbors a couple of hundred different bacterial species and those different types of bacteria increase or decrease in number in response to the composition of each meal.

Diversity of Plant Polysaccharides Provides Digestion Challenge
Plants provide the greatest challenge for digestion, because plants differ the most in their carbohydrate (sugars, oligosaccharides, polysaccharides) composition. Some of those carbs, such as sucrose, starch or the components of the plant cell walls, pectins, arabinogalactans and xyloglucans, are present in all vegetables. Whereas other polysaccharides, such as the sulfated porphyrans from red algae of the same name (Porphyra) are restricted to particular plants. Each different linkage and sugar requires a different digestive enzyme.

Gut Bacteria of Algae Eaters Have Algae-Degrading Enzymes
A recent report (see ref.) traced genes from marine bacteria that digest marine algae/seaweed, to gut bacteria of people who routinely eat seaweed. Researchers studying marine bacteria identified genes coding for new enzymes, porphyranases, that hydrolyzed porphyrans. When they checked gene databases for other porphyranase genes, they found that some gut bacteria had previously unassigned genes that were apparently, based on their nucleotide sequences, porphyranases. Curiously, these genes were only present in gut bacteria isolated from Japanese sources, i.e. from people who traditionally ate seaweed. In some of these bacteria there were more than 260 genes for degrading a huge variety of different plant polysaccharides.

Marine Bacteria on Seaweed Release DNA Incorporated into Gut Bacteria
Bacteria recognize that other bacteria are around by a process called quorum sensing. This signaling system triggers the production of matrix polysaccharides produced by the bacteria to hold the bacteria together in complex communities. Quorum sensing also mobilizes the release of copies of the bacterium’s genes, which is coordinated with uptake of DNA from the surrounding environment. [Note that the proteins that take in foreign DNA have basic amino acids arranged in the same heparin-binding domains that are also used by growth factors and their receptors or the numerous proteins that bind to nucleic acids in the nucleus or in ribosomes.] Thus, biofilm formation is accompanied by enhanced lateral gene exchange that would also enhance the incorporation of porphyranase genes from ingested marine bacteria.

Gut Bacteria Are Made in Guts and Shaped by Diet
Species of gut bacteria are defined in the micro lab by their ability to grow in Petri dishes of agar containing particular combinations of sugar, polysaccharides, etc. The sugars that different bacteria are able to metabolize for growth reflect sugars available as niches in different parts of the gut. Thus species are defined in part by the sugars and polysaccharides they can metabolize, i.e. by the enzymes they can produce.

In each human gut, however, bacteria of the species filling a particular niche will have many other additional genes than those that define the species. These atypical genes are present as a consequence of serendipitous encounters with genes from other bacteria (lateral gene transfer) and may reflect peculiarities of individual diets. Different regional cuisines also shape the regional gut flora. Persistent diet components would be expected to provide selective advantage for bacteria with genes capable of metabolizing new nutrients. Access to a rich diversity of bacterial genes to augment typical gut flora genomes will facilitate adaptation. Food processing to refine and simplify nutrient diversity, and hygiene to eliminate bacterial diversity in food, will reduce diversity in gut flora and minimize adaptation to novel foods. Antibiotics, especially persistent use, can permanently disrupt gut flora. Decreased diversity in gut flora may eliminate species of gut bacteria that are essential for normal physiological functioning of the gut and associated immune system, and may be major contributors to degenerative and autoimmune disease.

Thursday, April 1, 2010

Helminth therapy, i.e. infection with parasitic intestinal worms to provide remission from allergies, inflammatory bowel and other autoimmune diseases, has been examined as a potential therapeutic model to rehabilitate immunological dysfunction. The surface oligosaccharides of these worms have been found to mimic human oligosaccharides and alter immune responses by binding to carbohydrate-binding, i.e. lectin, receptors.

Immune Tolerance
The essence of allergic and autoimmune diseases is a defect in distinguishing between pathogen, innocuous and self molecules. Heightened immune reactions as a result of inflammation move the immune system toward production of antibody and T cell receptors specific for antigens. Those antigens respond to unique receptors on the surface of each B and T lymphocyte. The lymphocyte population has been previously depleted of cells that can produce receptors that will bind to most self antigens. This depletion makes the lymphocyte population generally non-responsive, or tolerant to self antigens. Thus, the immune system is blind to the body.

Regulatory T Cells and Tolerance
Most of the immune cells of the body are present in the lining of the gut. It is in the gut that various immune cells continue to develop for their various roles, including controlling immune reactions to self antigens and to common food molecules. Immune cells in the gut are exposed to some food molecules and bacteria that leak through the cells of the intestinal villi. Responding to these common antigens by inflammation can lead to inflammatory bowel disease. This pathological over-responsiveness is normally avoided by development of regulatory T cells, Tregs, that suppress immune responses to common food molecules and to surface antigens of common bacteria.

Treg Development Depends on Gut Flora
Gut bacteria are needed for the normal function of the immune system. Oddly, Helicobacter pylori, Hp, the cause of stomach ulcers and cancer, also stimulates the development of Tregs. Thus, the pathology of Hp may result not from its presence, but rather from how it is growing. Since Hp uses hydrogen gas produced by Klebsiella in the lower bowel and hydrogen production is dependent on dietary starch, then it follows that the pathological behavior of Hp may be dependent on dietary starch. A low starch diet may actually result in Treg stimulation from Hp and a reduction in allergies and autoimmune diseases.

Tregs Enhanced by Heliminths
Immunological tolerance is also stimulated by parasitic worms, Helminths. Helminth infestations, therefore, reduce allergies and autoimmune diseases and may contribute to the hygiene hypothesis to explain the prevalence of allergies, autoimmune and other inflammation-based degenerative diseases in modern societies. Examination of worms to find the molecules responsible for inducing immunological tolerance has identified complex surface and secreted oligosaccharides (small sugar chains) as the active molecules. Helminth oligosaccharides mimic human cell surface oligosaccharides and bind to carbohydrate-binding, lectin, receptors on immune cells to stimulate Treg development.

Lectin Receptors Control Tolerance
There are many implications of the modulation of the immune system via oligosaccharides. Note that related oligosaccharides are components of human milk and prepare the gut and develop the immune system. This explains why formula, which lacks these unique oligosaccharides, results in aberrant gut flora, contributes to neonatal necrotizing colitis and supports the development of allergies and autoimmune diseases. In contrast, judicious use of self or Helminth oligosaccharides may provide a means of restoring the function of damaged immune systems and therapy for allergies and autoimmune diseases. Also note that the critical use of lectins, which have oligosaccharide-binding sites rich in aromatic amino acids to bind the hydrophobic faces of the sugars, will also bind and provide entry into immune cells for allergens and autoantigens that have triplets of basic amino acids. The binding sites of lectins should also bind many aromatic phytochemicals. Immunomodulation by phytochemicals may result from interference with or mimicking the binding of oligosaccharides to lectin receptors.

Friday, March 19, 2010

Is Rosacea Caused by Amyloid LL-37, as Alzheimer’s Is Caused by Anti-microbial Abeta?
A recent article in PLoS One (Thanks Daniel!) suggests that the amyloid beta (Abeta) proteins that aggregate to form fibrous plaques in the brain tissue of Alzheimer victims, function as typical defensive anti-microbial peptides (AMPs), similar to the LL-37 cathelicidin implicated in facial tissue in rosacea. The structural and functional similarities of Abeta and LL-37 suggest to me that Alzheimer’s and rosacea may also be similar in initiation and treatment. Let’s compare amyloids and AMPs.

[The figure shows a model protein (from ref.) used to examine stain binding to amyloids. The stains appear to bind to aromatic amino acids spaced evenly between adjacent proteins, but adjacent basic amino acids (blue) are spaced the same way and provide sites for heparin binding.]

Some AMPs, e.g. LL-37, form fibers on DNA, heparin (stain with amyloid stains)

Toxic to cell membranes

Kallikrein stimulated by gut flora migrates to face and clips LL-37 to a smaller peptide that binds to host DNA and stimulates the TLR receptor to produce inflammation

Stomach pepsin hydrolyzes dietary proteins into anti-microbial peptides (heparin is secreted by mast cells onto to the intestinal surface to protect from any amyloid-like effects)

Defensins, cathelicidins and other AMPs are under transcriptional control of vitamin D receptor

Abeta Is Anti-microbial Like LL-37

Amyloid beta is the well-known source of the fibrous plaques forming brain lesions in Alzheimer’s disease. The normal function of Abeta has not been firmly established. The recent article shows data to support Abeta as an anti-microbial peptide comparable to LL-37 against several pathogenic bacteria and yeast. Knock-out mice deprived of a gene corresponding to Abeta are susceptible to bacterial infections. The anti-microbial activity present in extracts from Alzheimer’s disease brains was inactivated by anti-Abeta antibodies.

Implications of Abeta as an AMP Like LL-37

The similarities between AMPs and amyloid peptides suggest some implications for both Alzheimer’s disease and rosacea. Vitamin D is a hormone that binds to a cytoplasmic receptor and the vitD/receptor complex then acts as a transcription factor that controls the expression of defensins in the intestines, LL-37 in facial skin and perhaps Abeta in brains.

Amyloids form fibers on a scaffolding of heparan sulfate (HS). There is usually an excess of HS on the surface of cells and the HS is rapidly recycled back into cells. During inflammation, mast cells release heparin, short fragments of HS, that should also inhibit amyloid fiber formation on HS. Chronic inflammation, however, reduces HS production and may set the stage for amyloid fiber formation. HS metabolism of the brain may be vitally important to the development of Alzheimer’s disease, especially since the increasing chronic inflammation of aging people should deplete brain HS.

LL-37 forms complexes with DNA from damaged host cells in rosacea skin. The LL-37/DNA complexes trigger TLRs and inflammation. LL-37 may normally bind to cell surface HS and chronic inflammation of the skin may cause the shift to pathogenic autoinflammation. Topical application or perhaps low dose IV heparin may be effective in disrupting the autoinflammation due to LL-37. Part of the toxicity of LL-37 in the skin may be due to amyloid like structures that could form with inadequate HS and overabundant LL-37 production. Vitamin D metabolism should also be very important, since LL-37 synthesis is controlled by vitamin D. This is consistent with the benefits that some rosaceans observe with high doses of vitamin D3 supplements.

Friday, March 12, 2010

In previous articles, I have emphasized the mediation of extracellular signaling by heparan sulfate proteoglycans (HSPGs, polysaccharides attached to proteins) and heparin (HS fragments, oligosaccharides) and the sensitivity of HSPG expression and HS degradation by inflammation. I return to that subject, spurred on by reading two articles that together show both the significance of heparin-mediated growth factors in general and in the specific case of symptom development in rosacea.

FGF Receptor Inhibitors Cause Symptoms Like Rosacea
Fibroblast growth factors stimulate the development of cancers, and antibodies against FGF receptors block cancer growth (see ref.) FGF receptor inhibiting antibodies are now being used to stop cancers. Unfortunately, FGFR antibodies (e.g. cetuximab, panitumumab) also cause symptoms in the skin (telangiectasia, acneiform eruption) similar to the facial inflammation of rosacea. Similarly, in knock-out mice, that lack the ability to produce FGFR, there are related symptoms. It appears that lack of some FGF signaling may produce the symptoms of visible blood vessels and pus-filled (though lacking bacteria) follicles of rosacea.

FGF Mediated by HSPGFGF binds to the heparan sulfate of membrane bound HSPG in pairs and these FGF dimer/heparan sulfate complexes activate a pair of FGF receptors. The result is activation of protein phosphorylation activity (tyrosine kinase) and normal skin development. HSPG synthesis is modified by inflammation and heparanase activity is increased. This suggests that inflammation will decrease FGF signaling and could lead to symptoms of rosacea.

Growth Factors (VEGF, FGF) Bind to Heparin Nanofibers that Mimic Stem Cells
Stem cells produce lots of different growth factors and when stem cells are introduced into damaged cardiovascular tissue, more healing results (see ref.) To determine if the growth factors produced by the transplanted stem cells was sufficient for the improved healing, fibers made of heparin were dipped into stem cell cultures and the resulting growth factor-coated fibers were injected into damaged tissue. The heparin-binding growth factors were just as effective at enhancing healing as were the stem cells in previous experiments. This demonstrated that heparin-binding growth factors were the key to normal repair/revascularization and function.

Rosacea Results from Inflammation and Aberrant Vascularization
Rosacea is poorly understood and is probably numerous diseases that have related symptoms and complex development. As I indicated in previous articles, neurotransmitters from stimulated facial nerves, enzymes (kallikrein) and cytokines from intestinal interactions with gut flora, mast cell products (heparin, protease) and modified antimicrobial peptides (cathelicidins), as well as cryptic bacteria in facial tissues, may all be involved. Inflammation in the skin of the face and in the intestines is involved. Vitamin D, omega-3 fatty acids and anti-oxidants have a variety of responses (sometimes paradoxical) that differ from individual to individual and at different stages in the development of the disease. Facial inflammation leads to abnormal development of blood vessels (telangiectasia) and in accumulation of lymphocytes and neutrophils (papulopustular rosacea).

Facial Inflammation May Depress HSPG Production and Disrupt FGF Function
One of the key ramifications of persistent facial inflammation may be the depletion of of HSPGs that normally coat cells. HSPGs are continually produced, reabsorbed and degraded. The half-life for HSPGs, even those that surround the cells that produce cartilage in connective tissue, is six hours. HSPGs are also the source of heparin, that is produced as a counter ion bound to histamine and proteases in the secretory granules released by activated mast cells. Thus, inflammation-based depression of HSPG production, which is also accompanied by heparanase activation, will remove the HSPG coating of cells. This HSPG coating is needed for normal growth factor function. Lack of an HSPG matrix on the surface of cells will also result in the migration of growth factors away from where they are normally functional and into adjacent tissue where they may stimulate aberrant development of blood vessels. This may explain telangiectasia.

Is Topical Heparin a Rosacea Treatment?
Topical heparin does penetrate the skin. It would appear to be a logical treatment, if HSPG depletion is contributing to symptom development in rosacea. The length of the heparin fragments may be important. I am unaware if anyone has tried the heparin lotions that are available for treatment of wounds to minimize scarring, on rosacea. Heparin may be useful in combination with vitamin D3 and remediation of gut flora in a general scheme to treat rosacea.

Friday, March 5, 2010

A research paper in this week's Nature shows a major advance in the study of the role of the human gut flora in disease and health. Metagenomics of the Human Intestinal Tract (MetaHIT) Consortium examined the role of gut flora in health by a massive project (ref. below) to determine the DNA base sequence of the majority of the millions of genes in the thousands of species of bacteria that abide in human feces. Gut flora have been linked to many human diseases, as well as the normal function of the human immune system.

Major Findings:

576.7 gigabases sequenced (150 times larger than human genome)

Identified 3.3 million gut flora genes

Represents more than 1,000 bacterial species

Each individual harbors approx. 160 different species

Most prevalent species are identified and shared by everyone

Feces from 124 Europeans

Feces samples (124 individuals total) from a Danish project to determine the role of gut flora in obesity and from a Spanish project to determine the role of gut flora in Crohn’s disease and ulcerative colitis, were extracted for total DNA.

Illumina Multiplex Sequencing of PCR Amplified Fragments

DNA samples from each individual were fragments (<800 bp) and amplified to include indexing information and sequencing primers. The sequences of a dozen of the fragments at a time was determined using a dozen different dyes (Illumina multiplexing). Sample preparation and analysis was fully automated to permit identification of overlapping contiguous sequences and assembly of bacterial genomes (1,000-1,150 most common). The sequence data in this study represents most of the bacterial species of the gut.

Comparison to 89 Existing Human Gut Bacteria Genome Sequences

The new study represented more than 200 times the sequence information than in all previous studies combined. Existing genome sequences could be identified among the bacterial genomes assembled from the new data. The identified and sequenced bacterial species represent approximately a tenth of the common bacteria in the gut.

Polysaccharide/sugar Metabolism Common among Gut Flora

Genes coding for enzymes needed to metabolize pectin, sorbitol, mannose, fructose, cellulose and sucrose, were common among the gut flora. Bacteriophages were also significantly (5%) represented in the total gut metagenome. Most of the genes were assigned recognizable bacterial functions, but many genes, presumably involved in interactions among the bacterial community or in modification of gut function have not been characterized.

Obese, Crohn’s Disease, Ulcerative Colitis, Compared to Healthy

The bacterial gene compostion of individuals diagnosed with Crohn’s Disease and ulcerative colitis were different and distinct from healthy individuals. Individuals with Crohn’s disease had 25% fewer species of gut flora than comparable healthy controls.

This study demonstrates the feasibility of using current techniques to examine in detail the interactions between gut flora and tissues of the gut that are involved in health and disease. This also suggests the risks of antibiotics in altering critical functions of the gut flora, as well as the alteration of gut flora to support health and cure disease.

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About Me

I grew up in San Diego and did my PhD in Molecular, Cellular and Developmental Biology (U. Colo. Boulder). I subsequently held postdoctoral research positions at the Swedish Forest Products Research Laboratories, Stockholm, U. Missouri -Colombia and Kansas State U. I was an assistant professor in the Cell and Developmental Biology Department at Harvard University, and an associate professor and Director of the Genetic Engineering Program at Cedar Crest College in Allentown, PA. I joined the faculty at the College of Idaho in 1991 and in 1997-98 I spent a six-month sabbatical at the National University of Singapore. Most recently I have focused on the role of heparin in inflammation and disease.